ITT Analysis Research Articles

Motivational interviewing to enhance psychosocial treatment attendance in people with SMI

BackgroundWhile there is increasing support for the efficacy of psychosocial interventions for people with SMI, the real-world effectiveness of such treatments is diminished by lack of motivation for treatment, leading to poor treatment engagement/dropout. We sought to evaluate the efficacy of motivational interviewing (MI) in improving attendance in a full course of cognitive training, examine motivation level as a potential mechanism of action, and examine variables associated with initial engagement in the training. MethodsOne hundred fourteen participants with SMI were randomized to MI or sham control interview (CI), both of which were followed by a 4-month active phase during which participants could attend up to 50 unpaid cognitive training sessions. ResultsFidelity to the MI intervention was high, and MI condition was associated with increases in perceived value of training tasks and, to a lesser extent, how enjoyable/interesting they were rated. Twenty-nine percent of the full sample did not attend any training sessions. In ITT analyses, there was no significant between-group impact of MI on treatment attendance, though one emerged when participants who did not attend any sessions were excluded. Treatment attendance was predicted by the level of motivation achieved after the MI/CI intervention. Those who attended at least one training session (regardless of randomization) were more likely to believe they had cognitive impairments, had higher IQ and had less severe general psychiatric symptoms. ConclusionsMI showed some promise and may be a worthwhile addition to more comprehensive, robust efforts to promote initial treatment engagement and subsequent adherence.

Five-Year Structural Changes in the Knee Among Patients With Meniscal Tear and Osteoarthritis: Data From a Randomized Controlled Trial of Arthroscopic Partial Meniscectomy Versus Physical Therapy.

To estimate the risk of magnetic resonance imaging (MRI)-based structural changes in knee osteoarthritis (OA) among individuals with meniscal tear and knee OA, using MRIs obtained at baseline and 18 and 60 months after randomization in a randomized controlled trial of arthroscopic partial meniscectomy (APM) versus physical therapy (PT). We used data from the Meniscal Tear in Osteoarthritis Research (METEOR) trial. MRIs were read using the MRI OA Knee Score (MOAKS). We used linear mixed-effects models to examine the association between treatment group and continuous MOAKS summary scores, and Poisson regression to assess categorical changes in knee joint structure. Analyses assessed changes in OA between baseline and month 18 and between months 18 and 60. We performed both intention-to-treat and as-treated analyses. The analytic sample included 302 participants. For both treatment groups, more OA changes were seen during the early interval than during the later interval. ITT analysis revealed that, between baseline and month 18, APM was significantly associated with an increased risk of having a worsening cartilage surface area score, involving both any worsening across all knee joint subregions (risk ratio [RR] 1.35 [95% confidence interval (95% CI) 1.14, 1.61]) and the number of subregions damaged (RR 1.44 [95% CI 1.13, 1.85]) having a worsening effusion-synovitis score (RR 2.62 [95% CI 1.32, 5.21]), and having ≥1 additional subregion with osteophytes (RR 1.24 [95% CI 1.02, 1.50]). Significant associations were detected between months 18 and 60 only for having any subregion with a worsening osteophyte score (RR 1.28 [95% CI 1.04, 1.58]). These findings suggest that the association between APM and MRI-based structural changes in knee OA is most apparent during the initial 18 months after surgery. The reason for attenuation of this association over longer follow-up merits further investigation.

Amoxicillin-vonoprazan dual therapy for Helicobacter pylori eradication: A systematic review and meta-analysis.

The efficacy and safety of amoxicillin-vonoprazan (VA) dual therapy remained unclear. This systematic review was conducted in accordance with the PRISMA 2009 guidelines. A systematic search of the Pubmed, Embase, and Cochrane database was conducted using the combination of "Helicobacter pylori or H. pylori or Hp," "amoxicillin orpenicillin," and "Vonoprazan or TAK-438 or Takecab or (potassium AND competitive) or potassium-competitive." The initial and secondary outcome of this meta-analysis was to evaluate the efficacy and safety of VA dual therapy. Three studies and 668 H. pylori infected patients were included in this meta-analysis. The crude eradication rate of VA dual therapy was 87.5% and 89.6% by ITT and PP analysis, respectively. No significant differences were observed regarding the VA dual therapy and vonoprazan-amoxicillin-clarithromycin (VAC) triple therapy according to ITT (RR=0.99, 95% CI, 0.93-1.05, P=0.65) and PP (RR=0.99, 95% CI, 0.94-1.05, P=0.82) analysis. The side effect of VA dual therapy was 19.1% (95% CI, 5.9-32.4), which was lower than that of VAC triple therapy but there was no statistical significance (RR=0.75, 95% CI, 0.59-1.06, P=0.12). VA dual therapy shows acceptable efficacy, good safety and avoid unnecessary antibiotic use in the first-line treatment for H. pylori infection. However, its application in other regions need to be further explored.

Intent-to-Treat (ITT) vs Completer or Per-Protocol Analysis in Randomized Controlled Trials.

In randomized controlled trials, randomization creates groups that are reasonably well balanced on all baseline variables, whether measured, unmeasured, or unknown. Postbaseline events disturb this balance, resulting in postrandomization biases. Drop-out is one such event. There are two main methods for data analysis when there are dropouts. One method is to analyze data from only those who complete the study (completer analysis), or only those who complete the study and also comply with all its key elements (per-protocol analysis, a special type of completer analysis). The other method is to analyze the data from all randomized patients, regardless of dropout (intent-to-treat [ITT] analysis), or all randomized patients who meet an additional criterion, such as taking at least one dose of study drug (modified ITT [mITT] analysis, a special type of ITT analysis). Completer analyses present results in the ideal situation in which patients take medications as advised. ITT analyses present results related to real-world practice, where patients may be irregular with dosing or stop taking medications. The advantages and disadvantages of each type of analysis are discussed. The handling of missing data in ITT and mITT analysis is also briefly discussed.

Evaluation of the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age: The DESiGN cluster randomised trial.

Antenatal detection and management of small for gestational age (SGA) is a strategy to reduce stillbirth. Large observational studies provide conflicting results on the effect of the Growth Assessment Protocol (GAP) in relation to detection of SGA and reduction of stillbirth; to the best of our knowledge, there are no reported randomised control trials. Our aim was to determine if GAP improves antenatal detection of SGA compared to standard care. This was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial. Maternity units in England were eligible to participate in the study, except if they had already implemented GAP. All women who gave birth in participating clusters (maternity units) during the year prior to randomisation and during the trial (November 2016 to February 2019) were included. Multiple pregnancies, fetal abnormalities or births before 24+1 weeks were excluded. Clusters were randomised to immediate implementation of GAP, an antenatal care package aimed at improving detection of SGA as a means to reduce the rate of stillbirth, or to standard care. Randomisation by random permutation was stratified by time of study inclusion and cluster size. Data were obtained from hospital electronic records for 12 months prerandomisation, the washout period (interval between randomisation and data collection of outcomes), and the outcome period (last 6 months of the study). The primary outcome was ultrasound detection of SGA (estimated fetal weight <10th centile using customised centiles (intervention) or Hadlock centiles (standard care)) confirmed at birth (birthweight <10th centile by both customised and population centiles). Secondary outcomes were maternal and neonatal outcomes, including induction of labour, gestational age at delivery, mode of birth, neonatal morbidity, and stillbirth/perinatal mortality. A 2-stage cluster-summary statistical approach calculated the absolute difference (intervention minus standard care arm) adjusted using the prerandomisation estimate, maternal age, ethnicity, parity, and randomisation strata. Intervention arm clusters that made no attempt to implement GAP were excluded in modified intention to treat (mITT) analysis; full ITT was also reported. Process evaluation assessed implementation fidelity, reach, dose, acceptability, and feasibility. Seven clusters were randomised to GAP and 6 to standard care. Following exclusions, there were 11,096 births exposed to the intervention (5 clusters) and 13,810 exposed to standard care (6 clusters) during the outcome period (mITT analysis). Age, height, and weight were broadly similar between arms, but there were fewer women: of white ethnicity (56.2% versus 62.7%), and in the least deprived quintile of the Index of Multiple Deprivation (7.5% versus 16.5%) in the intervention arm during the outcome period. Antenatal detection of SGA was 25.9% in the intervention and 27.7% in the standard care arm (adjusted difference 2.2%, 95% confidence interval (CI) -6.4% to 10.7%; p = 0.62). Findings were consistent in full ITT analysis. Fidelity and dose of GAP implementation were variable, while a high proportion (88.7%) of women were reached. Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of clusters limits our ability to study small effect sizes. In this study, we observed no effect of GAP on antenatal detection of SGA compared to standard care. Given variable implementation observed, future studies should incorporate standardised implementation outcomes such as those reported here to determine generalisability of our findings. This trial is registered with the ISRCTN registry, ISRCTN67698474.

Ursodeoxycholic acid for the prevention of gallstones and subsequent cholecystectomy after bariatric surgery: a meta-analysis of randomized controlled trials.

This meta-analysis aimed to compare the incidence of gallstone formation, subsequent biliary disease and the need for cholecystectomy in untreated patients and patients treated with ursodeoxycholic acid (UDCA) following bariatric surgery. Randomized controlled trials (RCTs) comparing UDCA and controls for the prevention of gallstone formation after bariatric surgery published until February 2022 were selected and subjected to a systematic review and meta-analysis. Articles were searched in the MEDLINE, Web of Science and Cochrane Trials Register databases. Meta-analysis was performed with Review Manager 5.0. Eleven randomized controlled studies were included, with a total of 2363 randomized patients and 2217 patients analysed in the UDCA group versus 1415 randomized patients and 1257 patients analysed in the control group. Considering analysed patients, prophylactic use of UDCA was significantly associated with decreased (i) gallstone formation (OR = 0.25, 95% CI = 0.21-0.31), (ii) symptomatic gallstone disease (GD) (OR = 0.29, 95% CI = 0.20-0.42) and consequently (iii) cholecystectomy rate (OR = 0.33, 95% CI = 0.20-0.55). The results were similar in ITT analysis, in the subgroup of patients undergoing sleeve gastrectomy or considering only randomized versus placebo studies. Prophylactic use of UDCA after bariatric surgery prevents both gallstone formation and symptomatic GD and reduces the need for cholecystectomy.

Overall survival by IDH2 mutant allele (R140 or R172) in patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial.

7005 Background: IDH2 gene mutations (m IDH2) occur in up to ̃20% of patients (pts) with acute myeloid leukemia (AML), most commonly as R140Q (in ̃75% of cases) or R172K (̃25%) point mutations. The functional effects and prognostic relevance of m IDH2-R140 and m IDH2-R172 can vary (Papaemmanuil 2016). In the randomized, phase 3 IDHENTIFY trial, enasidenib (ENA), an oral mIDH2 inhibitor, did not significantly improve overall survival (OS) vs conventional care regimens (CCR) as salvage treatment (Tx) for older pts with m IDH2 relapsed/refractory (R/R) AML in ITT analysis, but a trend for improved OS with ENA was detected in pts with IDH2-R172 mutations. We further investigated OS and correlative biomarkers in IDHENTIFY pt subgroups defined by m IDH2 variant (R140/R172). Methods: This open-label trial (NCT02577406) enrolled pts ≥ 60 years of age who had received 2 or 3 prior AML Tx. Pts were preselected to a CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care), and were then randomized 1:1 to ENA 100 mg/d or CCR in 28d cycles. Co-occurring gene mutations were identified by targeted next-generation sequencing (37-gene panel) of bone marrow mononuclear cell (BMMC) DNA. Total 2-HG levels were determined by LC/MS. Results: Of 319 pts enrolled, 88 pts (28%; 43 ENA, 45 CCR) had m IDH2-R172 and 229 (72%; 115 ENA, 114 CCR) had m IDH2-R140. Median baseline (BL) 2-HG levels were similar between Tx arms and m IDH2 variant subgroups, as were IDH2 variant allele frequencies. Pts with m IDH2-R172 had fewer median BL co-mutations (4 [range 2–8]) than did pts with m IDH2-R140 (5 [1–11]) ( P &lt; 0.0001). The most frequently co-occurring mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with the R172 cohort, the R140 group was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2 mutations, whereas DNMT3A and TP53 mutations were more common in the R172 group. In Cox multivariate analysis including m IDH2 variant (R140/R172), DNMT3A mutation status, and number of gene mutations at BL, m IDH2-R172 was significantly ( P = 0.04) correlated with improved OS (vs. R140) in the ENA arm, whereas the number of BL gene mutations was significantly ( P &lt; 0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 mo with ENA vs 7.8 mo with CCR (HR, 0.59 [95%CI 0.35-0.98]; P = 0.039) and 1-yr survival rates were 62% and 30%, respectively. In m IDH2-R140 pts, median OS was 5.7 mo in both Tx arms (0.93 [0.70-1.24]; P = 0.61), and 1-year survival rates were 29% and 25% with ENA and CCR, respectively. Conclusions: Mutational burden and co-mutational profiles differed between pts with m IDH2-R140 and m IDH2-R172 R/R AML. ENA improved survival outcomes for pts with IDH2-R172 mutations, with median OS and 1-year survival rate approximately double those in the CCR arm. Clinical trial information: NCT02577406.

Early together: A randomized phase III study of early palliative care in metastatic uveal melanoma (MUM).

TPS9598 Background: Uveal melanoma is a rare cancer. Up to 50% of patients (pts) develop metastasis, mainly hepatic. Overall survival in metastatic pts is 12 months (mo), contrasting with a good overall condition until death. To evaluate the impact of integrating early palliative care on patient needs and self-efficacy, we designed a comparative randomized trial in MUM pts. Methods: 162 pts will be randomized (1:2) between the control and the experimental groups in two French centres (Institut Curie-Paris and Centre Antoine Lacassagne-Nice). In the control group, palliative care is introduced according to international guidelines. In the experimental group, it is added earlier, concomitant to the announcement of metastases by the medical oncologist. The main objective is to assess if early supportive care impacts on patient psychological needs at 6 mo, versus standard of care, based on the SCNS-SF34 questionnaire. Secondary objectives include patient’s other needs at 6 and 12 mo, quality of life (QLQ-C30), progression-free and overall survival, and partners’ needs (SCNS-P&amp;C). MUM pts, suitable for a treatment with no curative intent, ECOG PS 0-1, with no physical or biological sign of disease, and capable of filling questionnaires are eligible. Questionnaires are completed by all pts at each oncological visit (baseline, 3, 6, 9 and 12 mo). Supportive care visits take place every 6 weeks if needed and address patient’s information needs, disease and treatment understanding, social and psychological status, symptoms, and partners’ involvement. Prognostic uncertainty and disease seriousness in the absence of symptom is addressed depending on pts’ expressed needs. Medical oncologists and supportive care physicians from both centres attend communication skill training provided by an expert during the study. Analyses: SCNS-SF34 psychological needs scale scores at 6-mo will be compared with a Student’s t-test, in an ITT analysis. For 10 points mean score difference expected between groups (within standard deviation of 20 points) and a two-sided type 1 error of 5%, inclusion of 54 pts (control group) and 108 pts (experimental group) provides the study 85% of power. The planned inclusion period is 3 years, pts will be followed for one year, for a total study duration of 4 years. From July 2020 to January 2022, 63 pts have been enrolled in the trial; 2 pts declined. Five pts were removed early from the study: one for consent retrieval, 4 for early death due to metastasis. COVID-19 delayed enrollment for 5 months. We plan to complete the study Q4 2023 and to analyze the data Q4 2024. Clinical trial information: NCT04728113. [Table: see text]

Thrombocytopenic myelofibrosis (MF) patients previously treated with a JAK inhibitor in a phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) [MOMENTUM

7061 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials, including in MF patients (pts) with thrombocytopenia. MOMENTUM is a pivotal phase 3 study of symptomatic and anemic MF pts previously treated with a JAK inhibitor (JAKi) testing MMB vs DAN. This analysis evaluated MOMENTUM pts with baseline (BL) platelet counts (PLT) ≤150 x 109/L. Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb &lt;10 g/dL; prior JAKi for ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 weeks (wks) or Gr 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm; PLT ≥25 x 109/L. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks. Primary endpoint: TSS response (≥50% reduction from BL) rate at wk 24. Key secondary endpoints, assessed sequentially at wk 24: RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Results: 60 (74%) of 81 MMB pts and 25 (58%) of 43 DAN pts with BL PLT ≤150 x 109/L completed the 24-week randomized treatment (RT) phase. Median BL TSS were 29 (MMB) and 24 (DAN), Hgb were 7.9 (MMB) and 8.0 (DAN) g/dL, and PLT were 67 x 109/L (MMB) and 64 x 109/L (DAN). Prior JAKi was ruxolitinib in 124 pts (100%) and fedratinib in 6 pts (5%). Efficacy results are in Table. These results are consistent with the overall ITT analysis set (N=195). Most common Gr ≥3 TEAEs in the RT phase were thrombocytopenia (MMB, 31%; DAN, 16%) and anemia (MMB, 7%; DAN, 14%); Gr ≥3 bleeding events occurred in 9% of MMB and 5% of DAN pts. TEAEs led to study drug discontinuation in 15% of MMB and 19% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN [HR (95% CI)=0.490 (0.195, 1.235)]. Additional analyses of pts with BL PLT &lt;100 x 109/L (N=100) and BL PLT &lt;50 x 109/L (N=31) show similar treatment effects of MMB vs DAN. Conclusions: In thrombocytopenic MF pts who were symptomatic and anemic, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses and showed comparable safety and favorable survival. MMB may address a critical unmet need in thrombocytopenic MF pts. Clinical trial information: NCT04173494. [Table: see text]

Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes.

Introduction/AimsTrials incorporating placebo‐to‐active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank‐preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo‐controlled and open‐label extension (OLE) phases.MethodsIntent‐to‐treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed.ResultsHazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35–0.92) on ITT analysis and 0.39 (0.17–0.88) in the primary on‐treatment RPSFTM analysis (p = .023). Median ITT survival duration for PB and TURSO (25.8 mo) was 6.9 mo longer than placebo (18.9 mo) on ITT analysis and 10.6 mo longer than the median RPSFTM‐adjusted survival duration for placebo (15.2 mo). Median survival duration was 18.8 mo longer in the PB and TURSO–randomized subgroup who continued into the OLE phase versus the placebo‐randomized subgroup who did not continue into the OLE phase (p < .0001), although OLE phase selection bias may have potentially confounded these results.DiscussionSimilar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.

Effect of Early Psychological Counseling for the Prevention of Posttraumatic Stress Induced by Acute Coronary Syndrome at Long-Term Follow-Up.

ObjectivePsychological consequences of myocardial infarction (MI) are substantial, as 4% of all MI patients develop posttraumatic stress disorder (PTSD) and 12% clinically relevant posttraumatic stress symptoms (PTSS). The study investigated the course and development within 12 months of MI-induced PTSS to gain novel insights in potentially delayed response to early trauma-focused counseling aimed at preventing the incidence of MI-induced PTSS.MethodsIn the MI-SPRINT two-group randomized controlled trial, 190 MI-patients were randomly allocated to receive a single-session intervention of either trauma-focused counseling or an active control intervention targeting the general role of stress in patients with heart disease. Blind interviewer-rated PTSS (primary outcome) and additional health outcomes were assessed at 12-month follow-up.Results12-month follow-up of outcomes were available for 106 (55.8%) of 190 participants: In the entire sample, one patient (0·5%, 1/190) who received trauma-focused counseling developed full PTSD. There was no significant difference between trauma-focused counseling and stress counseling regarding total score of interviewer-rated PTSS (p > 0.05). The only group difference emerged in terms of more severe hyperarousal symptoms in the trauma-focused counseling group in the ITT analysis, but not in the completer analysis.ConclusionsNo benefits were found for trauma-focused counseling after 12 months when compared with an active control intervention. PTSD prevalence in the present study was low highlighting a potential beneficial effect of both interventions. Further studies are needed to determine the most accurate approach of counseling.

Reappraisal of the Medical Research Council Antiepileptic Drug Withdrawal Study: Contamination-adjusted and dose-response re-analysis.

ObjectiveThe 1991 Medical Research Council (MRC) Study compared seizure relapse for seizure‐free patients randomized to withdraw vs continue of antiseizure medications (ASMs). We re‐analyzed this trial to account for crossover between arms using contamination‐adjusted intention to treat (CA ITT) methods, to explore dose‐response curves, and to validate predictions against external data. ITT assesses the effect of being randomized to withdraw, as‐treated analysis assesses the confounded effect of withdrawing, but CA ITT assesses the unconfounded effect of actually withdrawing.MethodsCA ITT involves two stages. First, we used randomized arm to predict whether patients withdrew their ASM (logistic) or total daily ASM dose (linear). Second, we used those values to predict seizure occurrence (logistic).ResultsThe trial randomized 503 patients to withdraw and 501 patients to continue ASMs. We found that 316 of 376 patients (88%) who were randomized to withdraw decreased their dose at every pre‐seizure visit, compared with 35 of 424 (8%) who were randomized to continue (p < .01). Adjusted odds ratios of a 2‐year seizure for those who withdrew vs those who did not was 1.3 (95% confidence interval [CI] 0.9–1.9) in the as‐treated analysis, 2.5 (95% CI 1.9–3.4) comparing those randomized to withdraw vs continue for ITT, and 3.1 (95% CI 2.1–4.5) for CA ITT. Probabilities (withdrawal vs continue) were 28% vs 24% (as‐treated), 40% vs 22% (ITT), and 43% vs 21% (CA ITT). Differences between ITT and CA ITT were greater when varying the predictor (reaching zero ASMs) or outcome (1‐year seizures). As‐treated dose‐response curves demonstrated little to no effects, but larger effects in CA ITT analysis. MRC data overpredicted risk in Lossius data, with moderate discrimination (areas under the curve ~0.70).SignificanceCA ITT results (the effect of actually withdrawing ASMs on seizures) were slightly greater than ITT effects (the effect of recommend withdrawing ASMs on seizures). How these findings affect clinical practice must be individualized.

Statin use is associated with lower risk of dementia in stroke patients: a community-based cohort study with inverse probability weighted marginal structural model analysis

Current evidence is inconclusive on cognitive benefits or harms of statins among stroke patients, who have high risk of dementia. This observational cohort study investigated the association between statin use and post-stroke dementia using data from the Clinical Practice Research Datalink. Patients without prior dementia who had an incident stroke but received no statins in the preceding year were followed for up to 10 years. We used inverse probability weighted marginal structural models to estimate observational analogues of intention-to-treat (ITT, statin initiation vs. no initiation) and per-protocol (PP, sustained statin use vs. no use) effects on the risk of dementia. To explore potential impact of unmeasured confounding, we examined the risks of coronary heart disease (CHD, positive control outcome), fracture and peptic ulcer (negative control outcomes). In 18,577 statin initiators and 14,613 non-initiators (mean follow-up of 4.2 years), the adjusted hazard ratio (aHR) for dementia was 0.70 (95% confidence interval [CI] 0.64–0.75) in ITT analysis and 0.55 (95% CI 0.50–0.62) in PP analysis. The corresponding aHRITT and aHRPP were 0.87 (95% CI 0.79–0.95) and 0.70 (95% CI 0.62–0.80) for CHD, 1.03 (95% CI 0.82–1.29) and 1.09 (95% CI 0.77–1.54) for peptic ulcer, and 0.88 (95% CI 0.80–0.96) and 0.86 (95% CI 0.75–0.98) for fracture. Statin initiation after stroke was associated with lower risk of dementia, with a potentially greater benefit in patients who persisted with statins over time. The observed association of statin use with post-stroke dementia may in part be overestimated due to unmeasured confounding shared with the association between statin use and fracture.

Effects of inulin-type fructans with different degrees of polymerization on inflammation, oxidative stress and endothelial dysfunction in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial.

Polycystic ovary syndrome (PCOS) is associated with several cardiovascular risk factors. Prebiotics were proposed to beneficially affect risk factors associated with metabolic disorders. The aim of this study was to investigate and compare the effects of inulin-type fructans (ITFs), as well-studied prebiotics, with different degrees of polymerization, on markers of inflammation, oxidative stress and endothelial dysfunction in PCOS patients. A randomized, double-blind, placebo-controlled trial. Seventy-fivePCOS women were randomly assigned to receive 10 g/day of either high-performance inulin (HPI) or oligofructose-enriched inulin (OEI) or placebofor 12 weeks. Biochemical indices and blood pressure levelswere assessed before and after the intervention. In the intent-to-treat analysis, high-sensitive C-reactive protein (hs-CRP) decreased in HPI and OEI groups, over the 12 weeks, and the changes were significant in the HPI group, compared to placebo (changes from baseline in the HPI group: -0.11 vs. placebo group: 0.004 mg/L [conversion factor to SI units (nmol/L): 9/5238]; p = .007). Serum levels of nitric oxide (NO) increased, and endothelin-1and total oxidant statusdecreased in HPI and OEI groups, at the end of the trial; however, these changes were not significantly compared to placebo (p = .07, .36 and .22, respectively). No differences in systolic and diastolic blood pressure were found. Per-protocol analysis (n = 68) yielded consistent results for all endpoints, with the exception that the significant effect of ITFs on serum hs-CRP levels in the unadjusted ITT analysis became nonsignificant in the per-protocol analysis (p = .06). A 12-week supplementation with long-chain ITFs had favourable effects on inflammatory status among PCOS patients.

Initiation of antiretroviral therapy in treatment-naive adults with HIV infection at the first specialist appointment.

Fast initiation of ART has been associated with higher rates of retention in HIV care and viral suppression at 48 weeks and with lower mortality rates. However, scarce evidence exists in our setting, where diagnosis and treatment are carried out in different contexts. An observational retrospective study evaluating efficacy and safety of ART prescribed at the first specialist appointment, without baseline laboratory data, in a tertiary hospital in downtown Madrid. Individuals with a new diagnosis of HIV infection who initiated treatment at their first appointment with an infectious diseases specialist before receiving baseline laboratory results were included, irrespective of the ART regimen chosen. One hundred and eight participants were included. The majority (99.1%) were MSM who had acquired infection during sexual intercourse. The efficacy of ART, without baseline laboratory results at the time of initiation, was 85.2% (92/108) in the ITT analysis and 91.7% (99/108) in the treatment-related discontinuation equals failure analysis. All but nine patients presented an undetectable viral load (<50 copies/mL) at 48 weeks from starting ART. No serious adverse effects associated with the strategy were observed. In total, 101 participants continued care at 48 weeks with retention in HIV care rate of 93.5% (101/108). Initiating ART at the first available opportunity without baseline laboratory data does not reduce efficacy or safety of ART and achieves rapid virological control with high rates of retention in HIV care.

Immunological and inflammatory changes after simplifying to dual therapy in virologically suppressed HIV-infected patients through week 96 in a randomized trial

ObjectivesTo evaluate whether simplification of antiretroviral treatment to dual therapy (DT) negatively impacts immune recovery (IR), immune activation and inflammation (IA/I), and HIV reservoir. MethodsAn open-label, single-centre, randomized controlled trial conducted in adult virologically suppressed HIV-infected patients on triple therapy (TT) with elvitegravir-cobicistat, emtricitabine and tenofovir alafenamide or dolutegravir (DTG), abacavir, and lamivudine (3TC). Participants were randomized to continue TT or switch to DTG, or darunavir/cobicistat (DRVc) plus 3TC. IR was assessed by CD4+/CD8+ ratio at 48 and 96 weeks. Changes in immune activation, proliferation, exhaustion, senescence, and apoptosis in CD4+ and CD8+ T cells, plasma sCD14, hsCRP, D-dimers, β2-microglobulin, IL-6, TNF-α and IP-10 levels, cell-associated HIV-DNA (CA-DNA), and unspliced HIV-RNA (usRNA) were also analysed. ResultsOne hundred and fifty-one participants were enrolled. Fourteen patients did not complete the follow up. In the ITT and PP analysis, the IR was similar between the treatment arms. In the ITT analysis, the median increase in CD4+/CD8+ ratio was 0.10, 0.04, and 0.07 at week 48, and 0.09, 0.05, and 0.08 at week 96 for TT, DTG/3TC, and DRVc/3TC, respectively. After adjusting for confounding factors, the slopes of changes in CD4+/CD8+ ratio over time were independent of treatment (F = 1.699; p = 0.436) and related only to baseline values (F = 756.871; p = 0.000). There were no differences in IA/I, CA-DNA, or usRNA between treatment arms. DiscussionBoth IR and IA/I, CA-DNA, and usRNA were similar in the three treatment groups, regardless of maintaining TT or simplifying to DTG/3TC or DRVc/3TC in virologically suppressed HIV-infected patients.

The effect of Bacillus coagulans Unique IS-2 supplementation on plasma amino acid levels and muscle strength in resistance trained males consuming whey protein: a double-blind, placebo-controlled study.

The aim of the present study was to assess the effect of Bacillus coagulans Unique IS-2 supplementation on absorption and utilization of protein in resistance-trained males. In this double blind, placebo-control trial, resistance-trained males (21.08 ± 2.84years) were randomized to consume, either 20g of whey protein powder {80% whey protein concentrate (WPC80), amounting to 15.4g protein} with 2billion CFU Bacillus coagulans Unique IS-2 (supplemental group) or 20g of whey protein powder and lactose instead of Bacillus coagulans (placebo group) once daily for 60days with a controlled resistance exercise protocol. The whey protein concentrate (WPC-80) given to both groups had a lactose content of 6.8%. Plasma-free amino acids (PFAAs) were determined at baseline, at 30 and 60days of supplementation. Muscle strength, hypertrophy, VO2 max, and body composition, and other biochemical parameters were assessed at baseline and end line. A positive effect of probiotic Bacillus coagulans Unique IS-2 supplementation was observed on protein absorption as evidenced by an increase in total PFAA by + 16.1% (p = 0.004). Branched chain amino acids (BCAA) comprising isoleucine (p = 0.016), leucine (p = 0.001), and valine (p = 0.002) were increased by + 33.1% in ITT analysis as compared to placebo after 60days. At 30days an increase in isoleucine by + 35% (p = 0.113), leucine by + 43% (p = 0.032), and valine by + 32% (p = 0.017) was observed in ITT analysis. Probiotic effect was shown on exercise performance as evidenced by an increase in one RM of leg press and vertical jump power by + 16.61% (p = 0.024) and + 7.86% (p = 0.007), respectively. Significantly increased absorption of BCAA with supplementation of B. coagulans Unique IS-2 along with whey protein and improvement in leg press and vertical jump power was noted indicating the positive effect of the probiotic on muscle power in the lower body. CTRI/2017/03/008117; Date:16.03.2017.

Effect of enhanced patient instructions on Helicobacter pylori eradication: A systematic review and meta-analysis of randomized controlled trials.

To improve Helicobacter pylori (H. pylori) eradication rate, enhanced patient instructions (EPI) such as telephone-based re-education, short-message service, and Wechat have been proposed with conflicting results. The aim of this meta-analysis was to evaluate the effect of EPI on H. pylori eradication. The PROSPERO registered number of this study is CRD42021278536. PubMed, Embase, and CENTRAL database were searched to identify relevant randomized controlled trials (RCTs) from inception to September 2021. Meta-analysis was performed to estimate the pooled relative risk (RR) with 95% confidence intervals (CI) using a random-effects model. Trial sequential analysis (TSA) was conducted to determine the robustness of the H. pylori eradication rate. Nine RCTs were included. Compared with patients receiving only regular instructions, patients received EPI showed significantly higher H. pylori eradication rate (n=8 RCTs, ITT analysis: RR=1.20, 95% CI: 1.06-1.35; PP analysis: RR=1.12, 95% CI:1.02-1.23) and better patient compliance (n=8 RCTs, RR=1.23, 95% CI: 1.09-1.39), as well as higher patient satisfaction (n=3 RCTs, RR=1.42, 95% CI: 1.14-1.76). However, there were no significant difference between groups in the incidence of total adverse events (n=6 RCTs, RR=0.66, 95%CI: 0.40-1.08) and symptom relief rates (n=2 RCTs, RR=1.17, 95% CI: 0.89-1.54). The TSA result indicated that the effect was robust. Evidence from our meta-analysis shows that EPI intervention may be a promising strategy to improve H. pylori eradication rate, patient compliance, and patient satisfaction.

Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial

ObjectiveIn a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL. MethodsPhase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates. ResultsWithin 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ. ConclusionIn women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32.

Abstract P2-12-06: Pathological response-guided postoperative treatment strategy for positive HR/negative HER2 and positive lymphnodes breast cancer patients with non-responsive pathological results to neoadjuvant chemotherapy

Abstract Objective: No consensus up to date suggesting whether patients with positive HR/negative HER-2 and positive lymph nodes breast cancer should receive additional adjuvant chemotherapy following a poor response to neoadjuvant chemotherapy to acquire a better DDFS. The main aim of this trial is to compare the 5-year DDFS between additional adjuvant chemotherapy plus endocrine therapy group and endocrine alone group following 4 cycles neoadjuvant chemotherapy. Method: A multicenter, open-label, randomized, controlled, phase 3 trial was conducted. All patients enrolled in the study were HR+ HER2- LN+ breast cancer patients completing four cycles neoadjuvant chemotherapy, with a non-responsive pathological result to neoadjuvant chemotherapy. The non-responsive criterion was defined as Miller and Payne staging grade1 to grade 3, or any grade of Miller and Payne staging but residual positive lymph nodes were found in surgical specimen. All enrolled patients were randomly assigned to receive four cycles non-cross resistant regimen plus endocrine therapy, or endocrine therapy alone. The primary endpoint was DDFS, and the secondary endpoint was iDFS and OS. Result: From October 2010 to September 2018, a total of 391 patients were enrolled for eligibility. The final ITT analysis compromised 379 patients (187 in adjuvant chemotherapy plus endocrine therapy group, and 192 in endocrine therapy alone group). After a median follow-up of 72.4 months, the 5-year distant disease free survival estimate was 92% (95% CI 88-96) in the adjuvant chemotherapy group and 90% (86-94) in the endocrine therapy alone group (HR 0.79, 95% CI 0.45-1.37) (P=0.401). In the prespecified CEF subgroup, the 5-year DDFS was 94% (95% CI 90-98) in adjuvant chemotherapy group, and 91% (95% CI 87-94) in endocrine group (HR 0.68, 95% CI 0.36-1.30) (P=0.249). In the exploratory analysis, we found a better 5-year DDFS trend in adjuvant chemotherapy group in ypN+ patients in CEF subgroup (P=0.196). Conclusion: A better 5-year DDFS trend in additional adjuvant chemotherapy plus endocrine therapy can be found for patients with positive HR/negative HER-2 and positive lymph nodes following a poor response to neoadjuvant chemotherapy. Citation Format: Yang Yang, Xue Chen, Zhaoqing Fan, Yingjian He, Yuntao Xie, Jinfeng Li, Tianfeng Wang, Tao Ouyang. Pathological response-guided postoperative treatment strategy for positive HR/negative HER2 and positive lymphnodes breast cancer patients with non-responsive pathological results to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-06.